CN103814122B - Multiple analyte assay device and system - Google Patents

Multiple analyte assay device and system Download PDF

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Publication number
CN103814122B
CN103814122B CN201280033059.XA CN201280033059A CN103814122B CN 103814122 B CN103814122 B CN 103814122B CN 201280033059 A CN201280033059 A CN 201280033059A CN 103814122 B CN103814122 B CN 103814122B
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China
Prior art keywords
analyte
box
sensor
sample
signal
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CN103814122A (en
Inventor
J.J.德雷德
G.B.科利耶
S.A.霍夫斯塔德勒
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Aibis Biological Science Co Ltd
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Aibis Biological Science Co Ltd
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/5302—Apparatus specially adapted for immunological test procedures
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • G01N27/3271—Amperometric enzyme electrodes for analytes in body fluids, e.g. glucose in blood
    • G01N27/3273—Devices therefor, e.g. test element readers, circuitry
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54306—Solid-phase reaction mechanisms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2565/00—Nucleic acid analysis characterised by mode or means of detection
    • C12Q2565/60—Detection means characterised by use of a special device
    • C12Q2565/625—Detection means characterised by use of a special device being a nucleic acid test strip device, e.g. dipsticks, strips, tapes, CD plates
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/00029—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor provided with flat sample substrates, e.g. slides
    • G01N2035/00099—Characterised by type of test elements
    • G01N2035/00158—Elements containing microarrays, i.e. "biochip"

Abstract

A kind of technology relating to test organisms sample is provided herein, and particularly, but nonexclusively, relate to device, system and the external member chemically examined in real time the while of performing multiple with the disposable form of single use to sample.Such as, this technology relates to such as the equipment of point of care diagnostic, is included in the scene of the accident, emergency room, surgical operation, intensive care unit and non-medical applications and uses.

Description

Multiple analyte assay device and system
the cross reference of related application
This application claims the right of priority of the U.S.Provisional Serial 61/481,592 submitted on May 2nd, 2011, this patent application is merged into herein with way of reference in full.
Technical field
The invention provides a kind of technology relating to test organisms and/or environmental sample.Especially, device, system and the external member chemically examined in real time the while that this technology relating to for performing multiple to sample.Such as, this technology relates to the system for point of care diagnostic, is included in the scene of the accident, emergency room, surgical operation, intensive care unit and uses in non-medical applications.
Background technology
Biological or environmental sample are carried out to some laboratories test of analyte of interest for diagnosis, screening, staging, forensic analysis, conceived test, drug test and other reason.But these quantitative tests need the expertise of the well-trained technician in the laboratory situation using precision instrument mostly.In addition, laboratory test adds analysis cost and is delayed result.In most cases, postpone illness or the prognosis that can be unfavorable for patient, such as, to the analysis of the mark of instruction myocardial infarction.Under such critical situations and other situation, will advantageously in point-of care, carry out these analyses exactly, at an easy rate and with the minimum delay.
Some solutions to this problem are developed, such as use is configured to the disposable cassette of analysis single analyte and is configured to accommodating box, processing data and to user's display data portable, hand-held fetch equipment (referring to, such as U.S. Patent number No.7,419,821 and 5,096,669, be attached to herein in the mode that it quotes in full).The box of these routines has and the single input of reader communication and single output, such as, carrys out control analysis and shift the result data obtained with receiving and transmitting signal.But many molecular testings need the presence or absence of (or will benefit from) assessment multiple analytes or measure amount or the concentration of multiple analytes.These tests need multiple analyte sensor, and each being suitable for tests the single analyte in multiple analyte panel.Although box can be manufactured into the multiple sensors comprised for testing multiple analytes, data gathering needs to obtain live signal from each separated sensor.The solution of this problem for box and reader design are become to have multiple communication port, each sensor or tested analyte one.But due to many reasons, this solution does not cater to the need.First, such redesign can need to change form the electron device of the factor (such as, the size of box and/or reader and size) and/or box and fetch equipment.And then these changes can need the adjustment of the costliness in manufacturing installation and/or accept new system for user to cause obstruction then.Secondly, although disposable cassette is relatively inexpensive, fetch equipment is relatively costly.Therefore, user buys new fetch equipment to adapt to multiple analyte box by not wishing.Therefore, this field needs so a kind of measuring technology, i.e. to provide, the scene of multiple analytes is instant, real-time testing on the basis comprising the fetch equipment of an input and an output channel of its use previously installation.
Summary of the invention
In order to solve this problem, the invention provides a kind of technology of the multiple analytes related in test organisms sample.Especially, the invention provides device, system and the external member chemically examined in real time the while that a kind of disposable form for using with single performing multiple to sample, although also other form can be used.Such as, this technology relates to such as point of care diagnostic, comprises the equipment for the scene of the accident, emergency room, surgical operation, intensive care unit and non-medical applications.This technology comprises: disposable cassette, and it has one or more analyte sensor; Fetch equipment, it is suitable for accommodating box; And, for reader to control multiple sensor and/or the parts with multiple sensor communication via single output and single input channel (but if desired, also can use extra passage).
Therefore, in certain embodiments, technology provided by the present invention relates to a kind of box for sensing analyte in the sample to which, and this box comprises: multiple analyte sensor, and it is for sample for testing; Multiplexer, it is electrically connected to multiple analyte sensor; And data export, and it is electrically connected to multiplexer, and wherein, multiplexer receives multiple data signal from multiple analyte sensor; Encoded output signal, a part for the data signal received during output signal is included in time slot; And output signal is transferred to data output.In certain embodiments, box also comprises: for box being connected to the interface of fetch equipment.In various embodiments, interface comprises any mechanism in multiple different communication mechanism; Such as, in certain embodiments, interface comprises electrical connector and interface comprises mechanical fastener in certain embodiments.In certain embodiments, interface transmission signal between box and fetch equipment.In a particular embodiment, electrical connector is junctor chip.
This technology provides a kind of device, and it comprises for receiving, transmitting and the multiplexer of processing data and output signal.In certain embodiments, multiplexer is time division multiplexer.In certain embodiments, data signal is continuous data signal and outputs signal as discrete signal.
And, in certain embodiments, such as, in 0.01-0.1 second, during the time slot of 0.1-1 second or 1-10 second, produce output signal by carrying out digital sampling to data signal.Time slot is determined by any suitable parts or method.Such as, in certain embodiments, clock determination time slot, and in certain embodiments, control inputs determination time slot.Data can be transmitted in many ways, and such as, in certain embodiments, output signal comprises multiple passage, a part for the data signal received during wherein each passage is included in time slot.
Box comprises the multiple analyte sensors for detecting and/or measure multiple analytes.Such as, in certain embodiments, this box comprises: 10-100 analyte sensor, although be susceptible to more quantity and less quantity.Multiplexer is configured to process and send (route) signal from multiple sensor by route.In certain embodiments, multiplexer selects which data signal received from multiple analyte sensor encoded and send by route.
In addition, in certain embodiments, multiplexer also calculates dependent variable from multiple data signal, and therefore, in some embodiments of technology, output signal comprises the dependent variable of the multiple data signals calculating received from multiple analyte sensor.In certain embodiments, the data of individually and/or generally collecting are used for providing medical diagnostic information.In certain embodiments, there is medical condition in output signal denoted object, and in certain embodiments, output signal instruction does not exist medical condition in object.
In certain embodiments, multiplexer be used for from analyte sensor by route send data signals to export and be sent to fetch equipment in certain embodiments.There is process, coding, decoding, transmission, figure signal and/or select signal to carry out the many modes processing, encode, decode, transmit or convert.Such as, in certain embodiments, control inputs provides signal to indicate coding and to send which data signal received from multiple analyte sensor by route to multiplexer.In certain embodiments, box also comprises the demultplexer (demultiplexer) being electrically connected to multiple analyte sensor and the input being electrically connected to demultplexer.This technology is set to demultplexer in certain embodiments and receives input signal from input; Input signal is decoded as control signal; And, control signal is sent to analyte sensor by route.Control signal provides information and/or controls multiplexer and/or analyte sensor.Such as, in certain embodiments, control signal initial data signal from the transmission of analyte sensor and in certain embodiments control signal stop from analyte sensor transmission of data signals.In certain embodiments, control signal determination time slot.
This technology provides multiplex communication.Therefore, in certain embodiments, the data from multiple sensor are transmitted in multiplex format in single output.In certain embodiments, perform in the time domain multiplexed; Therefore, in certain embodiments, during time slot, such as, from analyte sensor transmission of data signals during the time slot of 0.01-0.1 second, 0.1-1 second or 1-10 second in certain embodiments.
In certain embodiments, device (such as, disposable apparatus) is for being configured to the system of the analyte sensed in sample.Therefore, the embodiment suitably provided in the present invention comprises the embodiment of described box and suitable fetch equipment.In some embodiments of system provided by the present invention, this box comprises: analyte sensor, and it is configured to analytic sample; Multiplexer, it is configured to receive data signal, Encoded output signal, and presses route transmission output signal; And, first interface parts, it is configured to coordinate with fetch equipment and communicate with fetch equipment; And wherein, fetch equipment comprises: the second interface unit, it is configured to coordinate with box and communicate with box; And microprocessor, it is configured to output signal to decode.Data signal transports data from electrochemical sensor to fetch equipment.In certain embodiments, the signal (such as, the output signal of decoding) of being decoded by microprocessor comprises the conversion of data signal or data signal.
The embodiment of system is configured to form interface with user and is connected, such as, to receive input from user and/or to transmit data or out of Memory to user.Therefore, in certain embodiments, this system also comprises user interface.
This system provides the technology of the multiple analytes in test sample.Such as, some embodiments are set to this system and comprise box, and box comprises multiple analyte sensor.In certain embodiments, multiple data signals that multiplexer is also configured to receive from multiple analyte sensor calculate dependent variable, and described output signal comprises dependent variable.Further, in some embodiments of this system, multiple data signals that microprocessor is also configured to receive from multiple analyte sensor calculate dependent variable.The system provided in the present invention is for assisted medical diagnosis.Therefore, in certain embodiments, in the output signal denoted object of decoding, there is medical condition, and in certain embodiments, there is not medical condition in the output signal instruction of decoding in object.
Device and system provide with external member, and it is user-friendly.Therefore some embodiments provide a kind of external member, and this external member comprises embodiment and the operation instruction of box described herein.In addition, some embodiments also comprise the equipment for collecting sample from object.External member also can comprise analysis software or carry out desired analysis use, need or be enough to carry out other parts any of desired analysis.
Based on instruction content comprised herein, Additional examples of composition will be apparent for those skilled in the art.
Accompanying drawing explanation
From accompanying drawing hereafter, these and other feature of this technology, aspect and advantage will become to be understood better:
The panel of the figure that Fig. 1 is the skeleton view (A) and top view (B) that show the embodiment of the box provided in the present invention.
Fig. 2 is the schematic diagram of the embodiment showing multiplex machine, it comprises box printed board unit, box printed board unit is connected to mixed printing circuit card by 18-pin connectors, and mixed printing circuit card is communicated with handheld device by serial communication interface.
Fig. 3 shows top view (A and C) and the fish-eye view (B and D) of the embodiment of the multiplexed box technology provided in the present invention.Fig. 3 A is the figure of the top view showing box, and Fig. 3 B is the top view of pcb board; Fig. 3 C is the figure of the fish-eye view showing box and Fig. 3 D is the fish-eye view of pcb board.
Embodiment
The technology provided in the present invention provides the device, system, external member and the correlation technique that are associated with multiple analyte sensor box, and in certain embodiments, provides and is suitable for accommodating box and the fetch equipment becoming interface to be connected with box-like.This box comprises multiplexer, and multiplexer is used for receiving data from multiple sensor and data being outputted to data exporting.Such technology is used for the field of such as medical diagnosis, for performing the test of Water demand more than a kind of analyte.
definition
For the ease of understanding this technology, define multiple term and phrase hereinafter.Additional definitions is set forth in whole detailed description.
" one ", " one " or " described " can represent one or more than one as used in this article.Such as, " one " widget can represent one or more widget.
" signal " is the time dependent amount be associated with by the one or more character of sample chemically examined as used in this article.Signal can be continuous print in time domain, or is discrete in time domain.As mathematical abstractions, continuous time signal territory is real number set (or its interval) and discrete-time signal territory is integer set (or its interval).Discrete signal usually produces via carrying out " digital sampling " to continuous signal.Such as, sound signal comprises the voltage of continued jitters on the line, and it is by reading voltage levvl on the line and digitizing with regular interval (such as every 50 microseconds).Several streams of gained are stored as discrete time digital signal.
Term " light " refers to the Energy Transfer form by vacuum or medium as defined herein, and wherein, magnetic field and electric field pass through vacuum or medium as wave traveling.And it can comprise visible ray, infrared rays and ultraviolet.Light can comprise single wavelength or multiple wavelength.One or more wavelength can in visible spectrum, in outer (such as in infrared or ultraviolet) of visible spectrum or its combination.The electromagnetic radiation that " although light " is human eye visible wavelength (from about 380 or 400 nanometers to the scope of about 760 or 780 nanometers), term used herein " light " is in this article for representing the electromagnetic radiation of visible or sightless any wavelength.
" light source " refers to that light enters the process of system as used herein.Such as, in some applications, light source is laser apparatus.Source can produce broadband or one or more different wavelength.In addition, this source can be launched output energy with single or multiple or export energy pulse or can scan a series of or continuous wavelength.
As used herein, the term, " object " and " patient " refers to any animal, such as dog, cat, bird, domestic animal and Mammals and preferably people especially.
" sample " broadly uses as the term is employed herein.In one sense, its intention comprises the representative part or substratum that obtain from any source, comprises biology and ambient source.Biological sample can obtain from animal (comprising people) and comprise fluid, solid, tissue and gas.Biological sample comprises blood products, such as blood plasma, serum etc.Environmental sample comprises environmentally conscious materials, such as terrestrial materials, soil, mud, mud, microbial film, water and production piece.But such example should not be understood to limit sample type used in the present invention.
As used herein, the term " analyte " be broadly interpreted as any compound, molecule or to be detected, identify or other material qualitatively.
" sensor " refers to sensing apparatus around as the term is employed herein, such as such as ion-sensitive and chemical-sensitive device, its existence based on analyte in tested sample or concentration and generate electrical signal (such as, electric current, electromotive force or electroconductibility).
Embodiment
Although in this article open with reference to some illustrate embodiment, should understand these embodiments in the illustrated manner instead of restriction mode provide.
1. box
This technology provides a kind of disposable cassette sample being performed to chemical examination.This box comprises one or more analyte sensor (such as, electrochemical analyte sensor and comprise one or more reference sensor in certain embodiments), export and send in certain embodiments the multiplexer of fetch equipment for keeping one or more chamber of fluid or other sample type and being sent to for the treatment of the signal received from analyte sensor and by data signal.In certain embodiments, this box comprises demultplexer, and it is from fetch equipment Received signal strength and signal is sent to analyte sensor by route.This box also comprises fluid management parts (such as, ingress port, outlet port, for measuring and provide the metering unit of concrete fluid volume, and for disposing and the pipeline of ship sample and other fluid) with at multiplexer, demultplexer, electrical connections that between fetch equipment and analyte sensor, transceiver electronics signal is required.
This box to be suitable for being inserted in fetch equipment and therefore to have multiple machinery and is connected for physically and electrically forming interface with fetch equipment with electrical connector.And, in certain embodiments, box comprises one or more chamber, wherein storing fluid, for such as washing sensor, is provided for the substrate of analysis (such as, for measuring enzymic activity), standard or the reference of analysis are provided, or some other fluids needed for analysis (such as, buffer reagent, amendment solution or some other solution) are provided.In the embodiment of box, fluid storage is in paper tinsel bag, and be inserted in after in fetch equipment at box, packing ring by pressure transmission on the paper tinsel bag comprising fluid, tip makes breakage of packing and execution measure before by fluid expulsion to being used for washing in the pipeline of sensor.
The embodiment of box presents many forms and configuration and they are made up of many suitable materials.Such as, quote in full with it example that mode U.S. Patent No. 7,419,821 be attached to herein provides the box that single uses.And, be disclosed in U.S. Patent No. 5,096 for the disposable sensing apparatus measuring the analyte in blood sample, 669, No.6,750,053, No.7,723, in 099.Other device is disclosed in U.S. Patent No. 5, and 628,961 and No.5,447, for measuring setting time in 440.These devices adopt fetch equipment and box, are box-packedly fitted in fetch equipment for measuring the change along with the time of analyte concentration in blood sample and viscosity.The embodiment of described box provides in the accompanying drawing of Fig. 1.
In certain embodiments, box is used for single sample.Use such box provide test sample facilitate mode, minimize sample contamination and carry-over risk simultaneously.Suitably, in certain embodiments, box is disposable.
2. multiplexer
Technology provided herein comprises multiplexer.Multiplexer is selected a kind of in some analog or digital input signals and selected input is forwarded to single circuit (such as, exporting).Therefore, be multiplexed as that (such as, physical transmission medium to transmit multiple signal combination) in common media be the method for a signal.Electronic multiplexer makes some signals can share a device or resource, such as, and output channel.Therefore, multiplexer can think multi input, single output switch.The multiplexed capacity by low-level communication port is divided into some high-level logical channels, each message signale to be transferred or data stream one.
Equally, demultplexer performs the inverse process being referred to as multichannel and distributing, with from the multiple passage of multiplexed signal extraction.Demultplexer can match with multiplexer and the multiplex signal of being encoded by multiplexer and transmit is decoded by demultplexer.Demultplexer also provides the technology sending multiple output signal spread out of from the single input signal spread out of.
Time division multiplex is that wherein two or more signals shift but the type of multiplexing in fact shifted in turn on passage as subchannel is apparent in a communication port simultaneously.Time domain is divided into the some recurrent time slot with regular length, each subchannel time slot.A part (such as, digital phantom, byte or data block) for subchannel 1 shifts during time slot 1, and a part (such as digital phantom, byte or data block) for subchannel 2 shifts during time slot 2.In certain embodiments, time division multiplex frame comprises a time slot and a synchronizing channel of each subchannel.And in certain embodiments, time division multiplex frame comprises error correction passage before the synchronization sometimes.After last subchannel, error correction and synchronizing channel, circulate with the repetition of new frame, start from the second section (such as, digital phantom, byte or data block) etc. from subchannel 1.If fully and carry out rapidly, receiving trap can not detect in circuit time some be used for another logical communication path.
3. sensor
Multiplexer process and send the signal received from multiple analyte sensor by route.In certain embodiments, sensor is electrochemical analyte sensor.Electrochemical analyte sensor exposes to sample to be assayed and reacts with sample to be assayed and generate the chemically active electrical signal (such as, electromotive force, electric current, electroconductibility) according to measured analyte.Such as, in certain embodiments, electrochemical analyte sensor generates the amount of analyte or the electromotive force (such as, potential determination sensor) of concentration per sample.Although do not limit the type of spendable sensor, be susceptible to this device and comprise the micro-manufacture sensor being applicable to the biomolecules producing and can detect wide range in batches.The example of such electrochemical analyte sensor is provided in U.S. Patent No. 4,613, and 422, No.4,739,380, No.4,933,048, No.5,063,081, No.5,200,051, No.5,837,446, No.5,837,454, No.6,030,827, No.6,379,883, No.7,540, in 948, be included in No.7,723, the reference sensor in 099, these modes quoted all are in full attached to herein for all objects.
In certain embodiments of the invention, be accessible signal by electrochemical component by analyte concentration transducing.These transverters can comprise measures electric current, potential determination (voltage determination) or electric conductance determination sensor.But this technology can comprise the transverter (such as, sound wave sensing apparatus, thermistor, gas sensing electrodes, field-effect transistor, light and evanescent field waveguide etc.) of other type.Can be used for the useful discussion of the transverter in sensor and list and the type of analytical applications that wherein transverter of every type or sensor can be used for usually sees in the Trends of Biotech.2 (3): 59-65 (1984), the disclosure and description wherein comprised are attached to herein for all objects with way of reference.In the three kinds of electroanalytical techniques mentioned before, potential determination and measurement current technique are preferred, because output signal can be easy to directly related for the response of specific analyte with sensor most.
In certain embodiments, electrochemical analyte sensor is used for detecting and/or quantizing analysis of immunogenicity thing.Analytical plan for detecting lower concentration analysis of immunogenicity thing relies on the formation of antibody/analyte/surface bound antibody " interlayer " mixture of enzyme labelling.Analyte concentration is in the sample to which converted into the ratio surface concn of enzyme.The chemical signal of enzyme by by substrate conversion being detectable product and Amplification Analysis thing.Such as, when alkaline phosphatase is enzyme, single enzyme molecule per minute can produce thousands of can detection molecules, with wherein detectable substance be attached to antibody replaces alkaline phosphatase scheme compared with, improve the detectability of analyte with some orders of magnitude.
In some embodiments of this detection technique, sensor detects the material producing electricity.The material producing electricity is before it is converted to electroactive substance by enzyme and electroinactive chemical part (moiety) or composition.The material of this non-activity is arranged in example reaction mixture and the character (such as, concentration, conformation, amount, oligomerisation state, bonding state etc.) being converted to activity form and analyte is associated and indicates the character of analyte.Such as, in certain embodiments, the material producing electricity is ferrocene deriv, p-aminophenol, hydrogen peroxide and/or ammonium ion.Should be appreciated that these examples are exemplary and this technology is not limited to for the generation electricity in sensor material.And in certain embodiments, enzyme generates this material producing electricity.Generate this example producing the enzyme of the material of electricity and include, but is not limited to alkaline phosphatase, glucose oxidase, Lactate Oxidase, L-GLOD, E.C. 1.1.99.1, rCO, alcohol oxidase, amyloglucosidase oxydase, lysyl oxidase, L-amino acid oxidase, Vitamin C oxidase, galactose oxidase and urase.In certain embodiments, the substance source of electricity is produced from catching with Nucleotide the enzyme reaction be associated.
In immunosensor embodiment, carry out the response of sensor at record before, sensor is advantageously made first to contact sample and then contact wash fluid.In a particular embodiment, utilize antibody-enzyme conjugate to revise sample, before the sample contacts sensor of amendment, antibody-enzyme conjugate is attached to the analyte of interest in sample.Association reaction in the sample to which produces analyte/antibody-enzyme complex.Sensor comprises the antibody be fixed on analyte near electrode surface attachment.When contact pickup, analyte/antibody-enzyme complex is attached to sessile antibody near electrode surface.Be conducive to removing unconjugated antibody-enzyme conjugate as much as possible to minimize the background signal of sensor from ate electrode at this point.The substrate conversion be arranged in fluid can be advantageously the material producing electrochemical activity by the enzyme of antibody-enzyme complex.This active substance produces near electrode and when applying suitable potential (measurement current practice), provides electric current from the redox reaction of electrode.Alternatively, if electroactive substance is ion, by potential determination, it is measured.In current measurement, that electromotive force can be fixed during measuring or change according to predetermined waveform.Such as, choppy sea can be used for the electromotive force scanned between the limit, as used in the cyclic voltammetric law technology known.Alternatively, digital technique, such as square wave can be used for improving the susceptibility detecting the electroactive substance adjacent with electrode.Measure from curtage, calculate amount or the existence of analyte in the sample to which.These and other analyzes electrochemical method is as known in the art.
On the one hand, technology provided by the invention provides a kind of sensor, and sensor comprises capture element and/or capture agent.Such element be preferentially with the specific objective of managing to be separated and to purify (such as, specifically and optionally) interactional molecule, partly, material or composition.For analyte target, there is desired binding affinity and/or specific any capture element can be used in this technology.Such as, capture element can be macromole, and such as peptide, protein (such as, antibody or acceptor), oligonucleotide, nucleic acid are (such as, the nucleic acid can hybridized with target nucleic acid), VITAMIN, oligosaccharides, carbohydrate, lipid or small molecules, or its mixture.As illustrative and non-limiting example, avidin target acquistion element can be used for the target that abstraction and purification comprises biotin moiety, antibody can be used for the target that abstraction and purification comprises suitable antigen or epitope, and oligonucleotide can be used for the oligonucleotide (such as, poly-dT oligonucleotide can be used for the target that abstraction and purification comprises poly-A afterbody) of abstraction and purification complementation.
Any nucleic acid, comprises target (such as, the product (such as PCR, RT-PCR, TMA, NASBA etc.) of amplified reaction that strand, double-strand and three chain nucleic acid are considered to catch; Genome or genomic fragment; Restriction fragment; RNA(is tRNA, mRNA, microRNA, siRNA, rRNA such as); Karyomit(e); Plasmid; Viral genome; Primer (primer); Gene).Permitted eurypalynous composition and/or be partly used as capture element.Such as, avidin capture element can be used to catch biotin labeled nucleic acid, or can catch by poly-dT capture element the nucleic acid comprising poly-A afterbody.In certain embodiments, nucleic acid is used as capture element.Can in conjunction with or any nucleic acid of combining target specifically, comprise the capture element that strand, double-strand and three chain nucleic acid can be used as in this device.The example of this nucleic acid comprises DNA, such as the DNA of A-, B-or Z-form; And RNA, such as mRNA, tRNA and rRNA; Aptamer; Peptide nucleic acid(PNA) and other amendment to sugar, phosphoric acid ester or nucleotide base.Therefore exist many strategies come target acquisition and accordingly those skilled in the art known permitted eurypalynous capture element.Although not limiting can the pattern of target acquisition nucleic acid, some embodiments of technology provided in this article comprise use oligonucleotide, oligonucleotide and target complementary and therefore by hybridizing and target acquisition with target nucleic acid specifically and optionally.Other embodiment uses other harvesting policy, such as antibody.
In addition, target acquistion element comprises location, concentrate, assemble the function such as capture element and therefore (such as, combine, hybridization etc.) is to capture element when catching time, the mode of abstraction and purification target is such as provided when formation target acquistion element complex.Such as, in certain embodiments, with the partial link of target (such as, oligonucleotide) interactional target acquistion element to solid support (such as, bead, surface, resin, post).Usually, solid support allows to use mechanical skill to come from heterogeneous solution separating and purification of target capture element mixture.
Also being susceptible to wherein sensor is the embodiment of optical sensor (such as photodetector).Photodetector detects light and produces electrical signal (such as, potential determination, measurement electric current or electric conductance determination signal).Light is correlated with the character of analyte measured in chemical examination or feature (such as, concentration, pH, conformation, activity, bonding state, redox state, oligomerisation state, amount etc.).The light detected is produced by multiple source and process.Such as, some chemical examinations of analyte produce light by fluorescence or cold light (biological example is luminous) and some chemical examinations comprise and use quantum dot and quantum dot produces light.In some chemical examinations, after light is by sample, detect light (such as, in the transmissivity or absorbefacient chemical examination (such as spectrophotometric chemical examination) of measure sample).
Optical sensor can configure by any way, and it allows the light property monitoring sample and/or analyte.Such as, some embodiments are set to sensor monitoring light intensity.For in spectrometric embodiment, sensor detects the light with the about phase co-wavelength of the wavelength incided on sample and/or analyte.In fluoroscopic examination embodiment, sensor monitoring is in the light intensity of the wavelength longer than the wavelength be incident on sample and/or analyte.Sensor comprises any appropriate technology for measuring light property.Such as, in certain embodiments, sensor is spectrometer.It is photovaristor, photovoltaic cell, photorectifier, photomultiplier, photocathode, photoelectric crystal, charge coupled device, reverse biased LED that Additional examples of composition is set to sensor.In certain embodiments, the one or more wavelength of sensor monitoring, and photodetector spectra re-recorded in certain embodiments.
4. analyte and sample
This technology is applicable to convenient and detection and quantitative measurment arbitrary number in real time various analyte substances.Such as, type or the classification of analyte include, but is not limited to ionophore, ion-exchanger, enzyme, biochemical metabolite, biological ion, breathing gas, antibody, antigen, lectin, neurochemical receptors, crystal, polypeptide, nucleic acid (such as, oligonucleotide, polynucleotide, Nucleotide, nucleosides, DNA molecular, RNA molecule), protein, Protein virus, toxin, peptide, sugar, lipid, steroid, salt, ion, glycoprotein, metalloprotein, cofactor, immunoglobulin (Ig) and other macromole with physiological significance, comprise mixture or active fragments or its subelement.Analyte can exist with unpack format or with the mixture of other material.In addition, analyte can with cell, tissue, microorganism (such as, live body, dead or lysate or from its other derivative composition), virus or other biomaterial or be associated from its derivative composition.Therefore, analyte is such as applicable to detect the existence of microorganism in sample, virus or particular cell types (such as, cancer cells, organization type) in certain embodiments.
The mark that the specific example being suitable for analyte includes, but is not limited to cTnI, CK-MB, bNP, TSH, hCG, PSA, thyroliberin, anti-core, thyroglobulin, anti-first gland medicament, anti-first gland medicament peroxidase and is associated with hepatitis, Rheumatoid factors, polyclonal, alzheimer's disease, atherosclerosis etc.
This technology is applicable to detect virus, such as HIV, HTLV, adenovirus, spore exanthema virus, poxvirus, parvovirus, picornavirus, togavirus, positive myxovirus, rhabdovirus, retrovirus and hepadnavirus etc.And this technology is applicable to the mark detecting pathogenic agent or be associated with Protein virus relative disease such as scrapie, chronic wasting disease and mad cow disease.
This technology is applicable to analyze most of liquid sample, comprise undiluted biological sample, such as whole blood, lymph, blood plasma, serum, saliva, urine, ight soil, sweat, mucus, tear, cerebrospinal fluid, nasal discharge, uterine cervix or vaginal secretions, seminal fluid, Pleural fluid, amniotic fluid, peritoneal fluid, middle ear effusion, synovial fluid, stomach aspirate etc.Should also be clear that solid or dry sample are dissolvable in water in appropriate solvent to provide the liquid mixture being suitable for analyzing.Multiplexed chemical examination can comprise collects similar analysis thing (such as, from the different IPs acid molecule of a variety of different organism) or different analyte (such as, having the nucleic acid etc. containing micromolecular peptide).
U.S. Patent No. 5,063,081 provides discussing in detail and experimental data of the some illustrative sensors being applicable to detect the analyte that following clinical is correlated with: glucose, base, blood urea nitrogen, uric acid, IgG, theophylline, cholesterol, 5-Triphosaden (ATP), creatinine, potassium ion, chlorion, sodium ion, pH etc.The embodiment of particularly suitable comprises part/ligand receptor base biosensor, and it is suitable for carrying out execution analysis based on intermolecular avidity and/or the interaction of immunochemistry mixture.Can design part/ligand receptor base chemical examination, wherein, one or the other member in mixture can be relevant analyte substance, and another component can be used as the fixing ligand receptor of sensor or immune-reactive substance.Therefore, part/ligand receptor base chemical examination can be suitable for analyte (such as, antigen/antibody, antibody/anti-antibody, vitamin H/avidin, immunoglobulin G/a-protein, enzyme/enzyme acceptor, ion/sequestrant, hormone/hormone receptor, substrate/enzyme, DNA(or RNA)/complementary polynucleotide sequence, the medicine/drug receptor etc. of measuring wider range).Be susceptible to such sensor to be especially suitable for carrying out assay thing by immunoassay.
Technology provided by the present invention is applicable to medical treatment, clinical and emergency medical service field.Therefore, in certain embodiments, this device is for chemically examining biological sample.In such chemical examination, biological sample comprises analyte and the character of analyte indicates this sample and the state of object taken from of this sample or character in certain embodiments.Some relevant samples include, but is not limited to whole blood, lymph, blood plasma, serum, saliva, urine, ight soil, sweat, mucus, tear, cerebrospinal fluid, nasal discharge, uterine cervix or vaginal secretions, seminal fluid, Pleural fluid, amniotic fluid, peritoneal fluid, middle ear effusion, synovial fluid, stomach aspirate, tissue homogenate, cell homogenates etc.Such as, for the object suffering from diabetes, sample is blood sample and analyte to be measured is glucose (such as, glucose concn).
And in certain embodiments, sample comprises or under a cloudly comprises the composition be associated with bioterrorism, biological example and/or chemicals.Biotechnological formulation is or is derived from live body, usual pathogenic organisms organism (such as, germ, virus, eukaryotic cell such as fungi or parasite).In certain embodiments, sample comprises biotoxin or is derived from other material biogenic (such as, small molecules, protein, Protein virus).Bioterrorism preparation is or is derived from biogenic; Therefore, biomarker-specific can be used for detecting them, such as nucleic acid, protein or identify biotechnological formulation and by suitable chemical examination, such as, utilize other small molecules that electrochemical analyte sensor detects.Such as, electrochemical analyte sensor can be used for detecting pcr amplification, the gene of virulence factor (such as, gene or protein), toxin or toxin-encoding generation and/or the mark that is associated with resistance.
Biotechnological formulation, some are militarily significant, include, but is not limited to: anthrax bacillus (pathogenic agent of anthrax); Staphylococcus; Ox brucella, sheep brucella and Brucella suis (pathogenic agent of brucellosis); Vibrio cholerae (pathogenic agent of cholera); Diphtheria corynebacterium (pathogenic agent of diphtheria); Cryptosporidium; Dysentery bacterium and intestinal bacteria (pathogenic agent of dysentery); Pseudomonas mallei (pathogenic agent of glanders); Listeria monocytogenes (pathogenic agent of listeriosis); Pseudoglanders Burkholderia (pathogenic agent of pseudoglanders); Plague bacillus (pathogenic agent of pestilence); Francisella tularensis (pathogenic agent of tularemia); Chlamydia psittaci (pathogenic agent of psittacosis); Coxiella burnetii (pathogenic agent of Q pyreticosis); Rickettsia rickettsii (pathogenic agent of Luo Ji mountain spot heat); Rickettsia prowazeki and typhoid fever rickettsia (typhic pathogenic agent); Posadasis spheriforme (pathogenic agent of coccidioidomycosis); East, western part and Venezuelan equine encephalitis (equine encephalitis pathogenic agent); Japanese encephalitis virus (pathogenic agent of Japanese encephalitis); Enzootic hepatitis virus (enzootic hepatitis pathogenic agent); Variola virus (smallpox pathogenic agent); Yellow fever virus (pathogenic agent of yellow jack); Arenavirus (pathogenic agent of lassa fever and Argentina, Bolivia, Brazil and Venezuelan hemorrhagic fever); Other viral pathogen of hemorrhagic fever; Other viral pathogen of Encephalitides; Marburg virus; Ebola virus; Nipah virus; Hantaan virus; SARS; H1N1 influenza virus.
And the biotoxin that may be used as biotechnological formulation includes, but is not limited to Ricin (being derived from Semen Ricini); Saxitoxin (being derived from dinoflagellate), staphylococcal enterotoxin B (being derived from streptococcus aureus); Tetraodotoxin (being derived from marine bacteria, such as vibrios kind and pseudoalteromonas); Single-ended spore mycotoxins (being derived from fungi, such as Fusarium, Trichoderma and grape ear mould); Novain (being derived from Clostridium botulinum); The general Shillong toxin (being derived from clostridium perfringens) of strategic point; Abrin (being derived from Semen Abri Precatorii).
Together with smallpox, anthrax, pestilence, sausage poisoning and tularemia, hemorrhagic fever virus are classified as by Center for Disease Control and Prevention (CDC) six kinds of preparations that most probable is used as chemical and biological weapons.Hemorrhagic fever virus includes, but is not limited to Arenaviridae (such as Lujo virus); Bunyaviridae (such as, Hantaan virus); Nairovirus (such as, Crimea-Congo hemorrhagic fever virus); Phlebovirus (Rift Valley fever virus); Inovirus section (such as, Ebola and Marburg virus); And flaviviridae (such as, singapore hemorrhagic fever, yellow jack, msk haemorrhagia fever virus and Ke Sanu forest virus).
Although this technology is when bioterrorism for detecting these and other preparation, this technology is also for detecting at other situation and the identical preparation in application and/or other preparation.Such as, this technology suffers from disease or the sample to other object that disease exposes for analyzing from sick patient or suspection.
5. fetch equipment
The embodiment of technology provided herein comprises fetch equipment, and fetch equipment is configured to receive test case (and therefore, this technology provides and to be configured to be inserted in fetch equipment and to form with fetch equipment the box that interface is connected).Fetch equipment is configured to send information to box and receive information from box.Such as, the chemical examination (utilizing electrochemical analyte sensor) that performed by box of these signal control and process the analysis data obtained from described chemical examination.In certain embodiments, fetch equipment comprises demultplexer, and it is decoded for the signal sent box.Such demultplexer can by software, firmware, be provided by application specific integrated circuit or its combination.The software and firmware that the current fetch equipment used by installed user base (base) performs for providing demultplexer ability can be upgraded.
Some embodiments of technology provided in this article also comprise collection, store and/or the function of analytical data.Such as, in certain embodiments, fetch equipment comprises treater, storer and/or database, and such as, for storing and performing instruction, analytical data, usage data performs calculating, transform data and storage data.In certain embodiments, fetch equipment is configured to the dependent variable calculating the data received from box (such as, from one or more electrochemical analyte sensor).In certain embodiments, fetch equipment comprises the software being configured to report medical treatment or clinical effectiveness, and equipment comprises the software for supporting non-clinical report the test in certain embodiments.
Many molecular testings relate to the presence or absence determining multiple analytes, or measure the amount of multiple analytes or concentration, and the equation comprising the variable of the character representing multiple analytes produces for making diagnosis or the existence of analysis and assessment thing or the value of quality.Therefore, in certain embodiments, fetch equipment calculates this value, and the user in certain embodiments to device shows this value, use this value to produce the instruction relevant to result (such as, LED, icon, sound etc. on LCD), store this value, transmit this value or use this value for extra computation.
In addition, in certain embodiments, treater is configured to control fetch equipment.In certain embodiments, treater is used for initial and/or stops measuring and data gathering.In certain embodiments, this device comprises user interface (such as, keyboard, button, scale card, switch etc.) for receiving user's input, and user's input will be used for instructing by treater and measure.In certain embodiments, this device also comprise for by data transmission (such as, by wired or wireless connection) to outside point of destination, the data of such as computer, indicating meter, network and/or exterior storage medium export.Some embodiments are set to device for less handheld portable devices, this incorporates these features and parts.The example of fetch equipment is provided in U.S. Patent No. 5,096, and 669 and No.5,821,399, its mode all quoted in full respectively with it is attached to herein for all objects.
example
The multiplexed analyte test box of 1.48 passage
Between the embodiment evolution period of technology provided in this article, develop and test the multiplexed analyte test box of 48-passage.Referring to such as Fig. 3.Box comprises printed circuit board (PCB) (PCB), printed circuit board (PCB) comprise testing circuit (such as, 48 detection of analytes electrodes, reference electrode and to electrode).Thick film processing is used to produce the PCB comprising testing circuit, but in certain embodiments, and the processing of non-used thick film produces the PCB comprising testing circuit.
Minimize by forming protective shielding widely around all sensitive lines or get rid of in the crosstalk such as between sensor and current carrying element.This reduce stray current such as by the chance of the augmentor measurement on mixing pcb board.In addition, by most of simulating signal is minimized or reduces noise being clipped in the internal layer between ground connection and power plane sends.In addition, the noise protecting trace and weighting material also to help to get rid of the low resistance due to its driving mechanism to cause.
Reference electrode is by silver/silver chloride being directly screen-printed to silver/silver chloride (Ag/AgCl) that PCB manufactures.At Ag/AgCl electrode and the routine techniques of silk screen printing, such as, between silver chloride metal electrode on the silicon die, do not observe marked difference.Electrode is provided for the local current return path of sensor electrode.Box comprises 48 sensors being arranged to 6 Parallel Simulation circuit (such as, 6 parallel measurement current channels), and each mimic channel comprises 8 working electrodes (such as, analyte sensor).Each detecting electrode is connected to switch (therefore, forming 48 switches altogether), and electrode is placed in on-off state by switch.In certain embodiments, switch is for improving performance and reducing size (such as, being minimized in footprint area required on PCB).Such as, in certain embodiments, Vishay/SiliconixDG612AEQ-T1-E3 switch is used for stepping register.
PCB circuit has 8 channel shift registers, and wherein each passage controls the switch of one group of 6 on/off, a switch in each measurement current channel.Therefore stepping register logical and disconnected one group of 6 switch simultaneously, a switch in each measurement electric current (analog current) passage.Therefore, 48 switches are subject to stepping register and control, and stepping register makes response with the break-make handover event realizing 48 switches and associated sensor for numerary signal (such as, being provided by microprocessor).Such as by switching with the speed of 2Hz, execution per second is measured and in 4 seconds, therefore reads whole 48 electrodes for 2 times, therefore, is collected in 5, each electrode place independently reading in 20 seconds.
Mixing pcb board forms interface by 18 pin connectors with box PCB and is connected.Mixing pcb board comprises 6 current measurement passages, and extremely digital (A/D) converting member of power regulation, microprocessor and simulation is to read signal and to send the data to equipment.Mixed plate PCB forms interface by serial communication interface with handheld device and is connected.Although the embodiment described in this example comprises the customized configuration of electrode, mixing pcb board can easily be redeployed as adaptation different electrode configurations.
As shown in FIG. 3, the embodiment of box comprises fluid bag, fluid pump and the port for Sample Injection.These parts are connected by microfluidic channel, and microfluidic channel is to the sensor sampling of electrode analysis thing and reagent, and electrode analysis thing sensor is along linear fluid path alignment.Box comprises the bus (such as, Hct bar, hematocrit (hematocrit) bar) along microfluidic channel, such as, with the existence of test fluid during microfluidic procedures.
Box comprises top cover and matrix, and it is made up of molded plastics in certain embodiments, and molded plastics provides the physical construction of supporting circuit and fluidic component.Metal, cardboard, paper, rubber and other material are in certain embodiments for top cover and for matrix.
In certain embodiments, box is designed to detect nucleic acid, such as pcr amplification.According to these embodiments, DNA acquisition sequence is chemically bound to the bead of 0.2 micron.Then bead is put the part be formed on as box production process on each sensor.
2. test the multiplexed analyte test box of 48 passage
Between the evolution period of the embodiment of the multiplexed analyte test box of 48 passage, collect test data.As the one application that this technology can be used for, perform test and detect nucleic acid existence (such as, the DNA amplification product (such as, " amplicon ") of auto-polymerization enzyme chain reaction).
These tests comprise use fluid test sample, and fluid test sample comprises the DNA structure with two parts: a part is the DNA with the DNA acquisition sequence complementation being attached to bead; And second section be attached on DNA can test section, biological example element.Binding substances (such as, comprising the streptavidin (such as ALP) being linked to enzyme) also adds in liquid sample.Streptavidin is attached to vitamin H and enzymatic lysis produces the substrate (such as, being also provided in test in sample) of electricity to produce the electronegativity material detected at electrode place.
For this test, the trapping nucleic acids bead point of single type is formed on all 48 sensors, and performs test to utilize sensor to detect amplicon.
Use the sampling rate (such as, 50ms is logical and 450ms is disconnected) of 2Hz, collect the data illustrating stable state low noise signal from each analog channel.In this particular, that each in 8 sensors in each analog channel is normally connected and in the analog channel of each supervision, 8 signals are added up.Then, by cutting off a switching channel of 8 channel shift registers (such as, comprise 6 switches, one, each passage in 6 mimic channel passages) and measurement measures the signal in each in particular sensor relative to the simulating signal change of resultant signal during whole 8 switch connections.Curent change is attributable to the levels of current cutting off (multiple) sensor.In other embodiments, each in 8 sensors in each analog channel is cut off usually, and by the switching channel (comprising 6 switches, one, each passage in 6 mimic channel passages) in connection 8 channel shift registers and each signal is measured in particular sensor in the simulating signal change of measuring zeroing (zeroed) signal when disconnecting relative to whole 8 switches.Curent change is owing to the levels of current of (multiple) sensor connected.In extra test, these two kinds of data acquisition schemes (such as, a sensor/passage is connected or sensor/passage disconnection) are compared, and two schemes obtains similar results.
At the embodiment test period of 48-sensor multiplexed array as described in this article, collected data (mean value measured for 10 times that such as, carry out for each sensor) indicate whole 48 sensors and obtain similar signal.These signal designations load with the consistent coverage (coverage) of the sensor of bead, consistent sample and collect 48 signals from 6 × 8 multiplexed sensor arraies.
At the embodiment test period of this technology, the data collected by 50ms handover event show signal Fast-Balance after handover event.Signal during handover event is consistent, regular and predictable.This allows to read signal by adopting correction coefficient before completing balance.Such as, in certain embodiments, the mathematical model for the signal response cutting off and connect handover event provides the switching frequency of increase (such as, being less than the interval of 50ms).Therefore, in certain embodiments, than 2Hz faster sampling rate be used in time per unit, gather more data.
The all open and patent mentioned in specification sheets is above attached to herein for all objects in the mode that it quotes in full.When not departing from the scope and spirit of described technology, the various modifications and variations of the composition of this described technology, method and purposes are apparent for those skilled in the art.Although expand description in conjunction with concrete exemplary embodiment to this technology, should be appreciated that the present invention for required protection should not be limited to these specific embodiments undeservedly.In fact, for pharmacy, biological chemistry, medical science or various equivalent modifications are apparent, described is expected within the scope of the appended claims for the various amendments performing pattern of the present invention.

Claims (19)

1., for sensing a box for analyte in the sample to which, described box comprises:
A) 48 analyte sensors;
B) 6 Measurement channel, it is electrically connected to described 48 analyte sensors;
C) 8 channel shift registers, it is electrically connected to described 48 analyte sensors;
D) multiplexer, it is electrically connected to described 48 analyte sensors; And
E) data export, and it is electrically connected to described multiplexer.
2. box according to claim 1, is characterized in that, analyte sensor is electrochemical analyte sensor or detects light and export the optical sensor of electrical signal.
3. box according to claim 1, is characterized in that, also comprise the interface for described box being connected to fetch equipment, wherein, described interface is transmission signal between described box and described fetch equipment.
4. box according to claim 1, is characterized in that, the output signal exported from described data comprises the sampling part of the data signal from analyte sensor.
5. box according to claim 1, is characterized in that, samples during the time slot of 0.01 to 10 second to data signal.
6. box according to claim 1, is characterized in that, is configured to collection per second 2 measurement.
7. box according to claim 1, is characterized in that, comprises the silver/silver chloride electrode of silk screen printing.
8. box according to claim 1, is characterized in that, comprises printed circuit board (PCB) further, and described printed circuit board (PCB) comprises described 48 analyte sensors.
9. box according to claim 1, is characterized in that, described analyte is selected from and comprises following group: nucleic acid, antigen, enzyme, protein, toxin, biochemical metabolite, biological ion and breathing gas.
10. box according to claim 1, is characterized in that, described analyte sensor produces the signal being selected from following classes or following classes combination: measure electric current, electric conductance determination and potential determination.
11. boxes according to claim 1, is characterized in that, the sensor in described multiple analyte sensor comprises trapping nucleic acids element.
12. boxes according to claim 1, is characterized in that, the sensor detection resources in described multiple analyte sensor catches the material of the generation electricity of the enzyme reaction be associated certainly with Nucleotide.
13. boxes according to claim 1, is characterized in that, described stepping register controls the on/off state of each analyte sensor in described 48 analyte sensors.
14. boxes according to claim 1, is characterized in that, each Measurement channel of described stepping register controls the on/off state of 6 analyte sensors simultaneously.
15. boxes according to claim 1, is characterized in that, a Measurement channel transports multiplex signal from 8 analyte sensors.
16. 1 kinds for sensing the system of analyte in the sample to which, described system comprises:
A) box according to claim 1; And
B) fetch equipment.
17. systems according to claim 16, is characterized in that, described box comprises:
1) analyte sensor, it is configured to analytic sample;
2) multiplexer, it is configured to receive data signal and output signal output; And
3) first interface parts, it is configured to coordinate with described fetch equipment and communicate with described fetch equipment; And
Wherein, described fetch equipment comprises:
1) the second interface unit, it is configured to coordinate with described box and communicate with described box; And
2) microprocessor, it is configured to described output signal decoding.
18. 1 kinds of external members, it comprises box according to claim 1.
19. 1 kinds for non-diagnostic and non-treatment object, for detecting the method for one or more analytes in the sample to which, comprising: box according to claim 1 is exposed to sample, and detects one or more analytes in described sample.
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